Pharmacokinetics of anti-Mycobacterium avium-intracellulare disease drugs in silkworms.

Pulmonary Mycobacterium avium-intracellulare complex (MAC) disease is a typical non-tuberculous mycobacterial infection. The incidence of pulmonary MAC is increasing worldwide. This study aimed to clarify the pharmacokinetic parameters of anti-pulmonary MAC disease drugs in silkworms. The pharmacokinetic parameters investigated included maximum concentration, area under the concentration-time curve, total clearance, and volume of distribution at steady-state. In addition, protein-binding rates, fat body transferability, and drug-drug interactions were examined. Antibiotic concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Among the antibiotics investigated, amikacin was not eliminated from silkworms during the 48-h observation period. In contrast, dose-proportional pharmacokinetics were observed in silkworms for all antibiotics tested, except for amikacin. Protein-binding rates in hemolymph for clarithromycin, azithromycin, rifampicin, ethambutol, and amikacin were 39.6 ± 3.0%, 39.5 ± 4.3%, 76.3 ± 3.2%, 20.9 ± 4.2%, and 73.1 ± 4.7%, respectively (mean ± standard deviation). The distribution of antibiotics in the fat bodies of silkworms was related to drug lipophilicity. No drug-drug interactions were observed in the silkworms. The pharmacokinetics of these drugs in silkworms differed significantly from those in humans. Therefore, while it is challenging to predict the pharmacokinetics of these drugs in humans based on silkworm data, the silkworm infection model has facilitated a comprehensive assessment of the relationship between antibiotic exposure and efficacy.

Plasma and Tissue Amikacin Concentrations Following Regional Limb Perfusion of Chickens (Gallus gallus domesticus).

Intravenous regional limb perfusion (IVRLP) has been used in the treatment of pododermatitis and distal limb infections, which are significant causes of morbidity in avian species. This intravenous drug administration technique is designed to achieve high drug tissue concentrations while minimizing systemic toxic effects. Amikacin is commonly used for IVRLP in veterinary medicine, but dosing guidelines have not been established for its use in birds. The current study aimed to determine the tissue concentration of amikacin after a single IVRLP administration in healthy, euhydrated leghorn hen chickens (Gallus gallus domesticus). Chickens received a single IVRLP dose of 10 mg/kg amikacin and were euthanatized posttreatment at 1 hour (n = 6), 12 hours (n = 6), and 24 hours (n = 6) to assess tissue and synovial fluid concentrations of amikacin in the injected leg. Mean tissue concentrations were highest 1 hour post-IVRLP (synovial fluid = 153.0 µg/mL, metatarsal pad tissue = 26.05 µg/mL) before declining at the 12- and 24-hour time points. This indicates that administration of amikacin via IVRLP can reach minimum inhibitory concentrations of common bacterial isolates in tissues after a single treatment with 10 mg/kg amikacin. Regional limb perfusion every 24 hours is recommended, although the minimum days of treatment may be case dependent and vary based on response to therapy.

P-gp inhibition and enhanced oral bioavailability of amikacin Sulfate: A novel approach using Thiolated Chito-PEGylated Lipidic Hybrids.

This study aimed to develop oral lipidic hybrids of amikacin sulfate (AMK), incorporating thiolated chitosan as a P-glycoprotein (P-gp) inhibitor to enhance intestinal absorptivity and bioavailability. Three formulations were designed: PEGylated Liposomes, Chitosan-functionalized PEGylated (Chito-PEGylated) Lipidic Hybrids, and Thiolated Chito-PEGylated Lipidic Hybrids. The physical characteristics of nanovesicles were assessed. Ex-vivo permeation and confocal laser scanning microscopy (CLSM) studies were conducted to evaluate the formulations' potential to enhance AMK intestinal permeability. In-vivo pharmacokinetic studies in rats and histological/biochemical investigations assessed the safety profile and oral bioavailability. The AMK-loaded Thiolated Chito-PEGylated Lipidic Hybrids exhibited favorable physical characteristics, higher ex-vivo permeation parameters, and verified P-gp inhibition via CLSM. They demonstrated heightened oral bioavailability (68.62% absolute bioavailability) and a sufficient safety profile. Relative bioavailability was significantly higher (1556.3% and 448.79%) compared to PEGylated Liposomes and Chito-PEGylated Lipidic Hybrids, respectively, indicating remarkable oral AMK delivery with fewer doses, reduced side effects, and enhanced patient compliance.

Faster perfusate instillation time results in more systemic leakage of amikacin sulfate when performing intravenous regional limb perfusion in horses.

OBJECTIVE: To evaluate if a difference in synovial amikacin concentrations exists in the radiocarpal joint (RCJ) following different durations of instillation of an IV regional limb perfusion (IVRLP) perfusate. ANIMALS: 7 healthy horses. METHODS: Horses received 2 IVRLPs with 2 g amikacin diluted to 60 mL with 0.9% NaCl via the cephalic vein in a crossover study design with a wash-out period between procedures. Instillation of the perfusate was administered over a 1-minute (technique 1) and 5-minute (technique 5) period. Concentrations of amikacin within the RCJ were measured at time (T) 5, 10, 15, 20, 25, and 30 minutes after instillation of the perfusate. Systemic concentrations of amikacin were measured at T0, 5, 10, 15, 20, 25, 29 minutes, and 1 minute after tourniquet removal (T31). Amikacin concentrations were determined by fluorescence polarization immunoassay. RESULTS: The median maximum concentration (CMAX) of amikacin within the RCJ for technique 1 was 338.4 µg/mL (range, 60 to 4,925 µg/mL), while the median CMAX for technique 5 was higher at 694.8 µg/mL (range, 169.2 to 3,410 µg/mL; P = .398). There was a higher amikacin blood concentration over time for technique 1 compared to technique 5 (P = .004). CLINICAL RELEVANCE: Administration of perfusate at different rates did not significantly affect synovial concentration of amikacin within the RCJ when performing IVRLP. However, increased systemic leakage was noted when the perfusate was administered over 1 minute, which might affect synovial concentrations in a larger group of horses.

Pharmacokinetics of amikacin after intravenous, intra-articular, and combined intravenous and intra-articular administration in healthy neonatal foals.

BACKGROUND: Pharmacokinetics of amikacin administered IV to neonatal foals are described, but little data are available regarding the plasma concentrations contributed by concurrent intra-articular (IA) administration. HYPOTHESIS/OBJECTIVES: Compare the pharmacokinetics of amikacin when the total dose is administered IV compared to being divided between IV and IA routes of administration in neonatal foals and predict the plasma concentrations from various combined IV and IA dosing regimens. ANIMALS: Eight healthy neonatal foals. METHODS: Foals received 3 amikacin treatment protocols: (1) IV-only (25 mg/kg q24h IV), (2) concurrent IV and IA (16.7 mg/kg q24h IV and 8.3 mg/kg q24h into 1 tarsocrural joint), and (3) IA-only (8.3 mg/kg q24h into 1 tarsocrural joint). Protocols were administered for 3 days beginning at 7, 14, and 21 days of age. Plasma concentrations ≥53 µg/mL at 30 minutes were considered therapeutic for isolates with intermediate susceptibility. RESULTS: Foal age was a significant variable. The IV-only protocol met or exceeded the 30-minute plasma concentrations considered therapeutic (mean µg/mL [95% confidence interval, CI]) in 7- to 9-day-old (54.0 [52.2-56.9]), 14- to 16-day-old (58.1 [55.2-61.0]), and 21- to 23-day-old (66.6 [63.7-69.6]) foals. Concurrent IV and IA protocol did not reach the 30-minute concentration considered therapeutic in 7- to 9-day-old foals (46.5 [43.6-49.4]) but did in 14- to 16-day-old (62.9 [60.0-65.8]) and 21-to 23-day-old (62.6 [59.7-65.6]) foals. CONCLUSIONS AND CLINICAL IMPORTANCE: Concurrent IV and IA administration of amikacin produces 30-minute plasma concentrations considered therapeutic in foals 14 to 23 days old, but concentrations observed in younger foals might be below those considered therapeutic for isolates with intermediate susceptibility to amikacin.

Pharmacometric in silico studies used to facilitate a national dose standardisation process in neonatology - application to amikacin.

BACKGROUND AND AIMS: Pharmacometric in silico approaches are frequently applied to guide decisions concerning dosage regimes during the development of new medicines. We aimed to demonstrate how such pharmacometric modelling and simulation can provide a scientific rationale for optimising drug doses in the context of the Swiss national dose standardisation project in paediatrics using amikacin as a case study. METHODS: Amikacin neonatal dosage is stratified by post-menstrual age (PMA) and post-natal age (PNA) in Switzerland and many other countries. Clinical concerns have been raised for the subpopulation of neonates with a post-menstrual age of 30-35 weeks and a post-natal age of 0-14 days ("subpopulation of clinical concern"), as potentially oto-/nephrotoxic trough concentrations (Ctrough >5 mg/l) were observed with a once-daily dose of 15 mg/kg. We applied a two-compartmental population pharmacokinetic model (amikacin clearance depending on birth weight and post-natal age) to real-world demographic data from 1563 neonates receiving anti-infectives (median birth weight 2.3 kg, median post-natal age six days) and performed pharmacometric dose-exposure simulations to identify extended dosing intervals that would ensure non-toxic Ctrough (Ctrough <5 mg/l) dosages in most neonates. RESULTS: In the subpopulation of clinical concern, Ctrough <5 mg/l was predicted in 59% versus 79-99% of cases in all other subpopulations following the current recommendations. Elevated Ctrough values were associated with a post-natal age of less than seven days. Simulations showed that extending the dosing interval to ≥36 h in the subpopulation of clinical concern increased the frequency of a desirable Ctrough below 5 mg/l to >80%. CONCLUSION: Pharmacometric in silico studies using high-quality real-world demographic data can provide a scientific rationale for national paediatric dose optimisation. This may increase clinical acceptance of fine-tuned standardised dosing recommendations and support their implementation, including in vulnerable subpopulations.

Design and development of dual drug-loaded nanofibrous inserts for ophthalmic sustained delivery of AMK and VAN: Pharmacokinetic study in rabbit's eye.

Bacterial corneal keratitis is a damage to the corneal tissue that if not treated, can cause various complications like severe vision loss or even blindness. Combination therapy with two antibiotics which are effective against Gram-positive and Gram-negative bacteria offers sufficient broad-spectrum antibiotic coverage for the treatment of keratitis. Nanofibers can be a potential carrier in dual drug delivery due to their structural characteristics, specific surface area and high porosity. In order to achieve a sustained delivery of amikacin (AMK) and vancomycin (VAN), the current study designed, assessed, and compared nanofibrous inserts utilizing polyvinyl alcohol (PVA) and polycaprolactone (PCL) as biocompatible polymers. Electrospinning method was utilized to prepare two different formulations, PVA-VAN/AMK and PCL/PVA-VAN/AMK, with 351.8 ± 53.59 nm and 383.85 ± 49 nm diameters, respectively. The nanofibers were simply inserted in the cul-de-sac as a noninvasive approach for in vivo studies. The data obtained from the physicochemical and mechanical properties studies confirmed the suitability of the formulations. Antimicrobial investigations showed the antibacterial properties of synthesized nanofibers against Staphylococcus aureus and Pseudomonas aeruginosa. Both in vitro and animal studies demonstrated sustained drug release of the prepared nanofibers for 120 h. Based on the in vivo findings, the prepared nanofibers' AUC0-120 was found to be 20 to 31 times greater than the VAN and AMK solutions. Considering the results, the nanofibrous inserts can be utilized as an effective and safe system in drug delivery.

Population pharmacokinetics and humanized dosage regimens matching the peak, area, trough, and range of amikacin plasma concentrations in immune-competent murine bloodstream and lung infection models.

Amikacin is an FDA-approved aminoglycoside antibiotic that is commonly used. However, validated dosage regimens that achieve clinically relevant exposure profiles in mice are lacking. We aimed to design and validate humanized dosage regimens for amikacin in immune-competent murine bloodstream and lung infection models of Acinetobacter baumannii. Plasma and lung epithelial lining fluid (ELF) concentrations after single subcutaneous doses of 1.37, 13.7, and 137 mg/kg of body weight were simultaneously modeled via population pharmacokinetics. Then, humanized amikacin dosage regimens in mice were designed and prospectively validated to match the peak, area, trough, and range of plasma concentration profiles in critically ill patients (clinical dose: 25-30 mg/kg of body weight). The pharmacokinetics of amikacin were linear, with a clearance of 9.93 mL/h in both infection models after a single dose. However, the volume of distribution differed between models, resulting in an elimination half-life of 48 min for the bloodstream and 36 min for the lung model. The drug exposure in ELF was 72.7% compared to that in plasma. After multiple q6h dosing, clearance decreased by ~80% from the first (7.35 mL/h) to the last two dosing intervals (~1.50 mL/h) in the bloodstream model. Likewise, clearance decreased by 41% from 7.44 to 4.39 mL/h in the lung model. The humanized dosage regimens were 117 mg/kg of body weight/day in mice [administered in four fractions 6 h apart (q6h): 61.9%, 18.6%, 11.3%, and 8.21% of total dose] for the bloodstream and 96.7 mg/kg of body weight/day (given q6h as 65.1%, 16.9%, 10.5%, and 7.41%) for the lung model. These validated humanized dosage regimens and population pharmacokinetic models support translational studies with clinically relevant amikacin exposure profiles.

A physiological approach to renal clearance: From premature neonates to adults.

AIMS: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance. METHODS: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution. RESULTS: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug-specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50-5.69) (gentamicin), 7.77 L/h (95% CI 7.26-8.19) (amikacin) and 4.70 L/h (95% CI 4.61-4.80) (vancomycin). CONCLUSIONS: GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention.

Development and application of neonatal physiology-based pharmacokinetic models of amikacin and fosfomycin to assess pharmacodynamic target attainment.

Antimicrobial resistance increasingly complicates neonatal sepsis in a global context. Fosfomycin and amikacin are two agents being tested in an ongoing multicenter neonatal sepsis trial. Although neonatal pharmacokinetics (PKs) have been described for these drugs, the physiological variability within neonatal populations makes population PKs in this group uncertain. Physiologically-based pharmacokinetic (PBPK) models were developed in Simcyp for fosfomycin and amikacin sequentially for adult, pediatric, and neonatal populations, with visual and quantitative validation compared to observed data at each stage. Simulations were performed using the final validated neonatal models to determine drug exposures for each drug across a demographic range, with probability of target attainment (PTA) assessments. Successfully validated neonatal PBPK models were developed for both fosfomycin and amikacin. PTA analysis demonstrated high probability of target attainment for amikacin 15 mg/kg i.v. q24h and fosfomycin 100 mg/kg (in neonates aged 0-7 days) or 150 mg/kg (in neonates aged 7-28 days) i.v. q12h for Enterobacterales with fosfomycin and amikacin minimum inhibitory concentrations at the adult breakpoints. Repeat analysis in premature populations demonstrated the same result. PTA analysis for a proposed combination fosfomycin-amikacin target was also performed. The simulated regimens, tested in a neonatal sepsis trial, are likely to be adequate for neonates across different postnatal ages and gestational age. This work demonstrates a template for determining target attainment for antimicrobials (alone or in combination) in special populations without sufficient available PK data to otherwise assess with traditional pharmacometric methods.

Therapeutic drug monitoring of amikacin in preterm and term neonates with late-onset sepsis. Can saliva samples replace plasma samples?

Amikacin is an aminoglycoside antibiotic that is frequently used for the treatment of neonatal late-onset sepsis, for which therapeutic drug monitoring (TDM) is advised. In order to decrease the TDM associated burden of plasma sampling, a noninvasive TDM method using saliva samples was investigated. METHODS: This was a prospective single-centre, observational feasibility study with 23 premature and term neonates from whom up to 8 saliva samples were collected, together with residual plasma from clinical routine. Amikacin concentrations in saliva and plasma were quantified with liquid chromatography-tandem mass spectrometry. A population pharmacokinetic analysis was performed to develop an integrated pharmacokinetic model of amikacin in plasma and saliva and for the identification of covariates. TDM performance of different sampling regimens was evaluated using Monte Carlo simulations in a fictional cohort of representative neonates (n = 10 000). RESULTS: Amikacin could be detected in saliva and a saliva compartment was appended to a 2-compartment plasma model. First-order absorption (k13 ) of the saliva compartment was 0.0345 h-1 with an interindividual variability of 45.3%. The rate of first-order elimination (k30 ) was 0.176 h-1 . Postmenstrual age had a significant negative covariate effect on k13 , with an exponent of -4.3. Target attainment increased from 77.6 to 79.2% and from 79.9 to 83.2% using 1-to 5 saliva samples or 1-5 plasma samples, respectively. CONCLUSION: TDM of amikacin using saliva samples results in target attainment comparable to plasma samples and may be beneficial for (premature) neonates with late-onset sepsis.

Population pharmacokinetics of amikacin in suspected cases of neonatal sepsis.

AIMS: This study aimed to characterize the population pharmacokinetic parameters of intravenously administered amikacin in newborns and assess the effect of sepsis in amikacin exposure. METHODS: Newborns aged ≥3 days who received at least 1 dose of amikacin during their hospitalization period were eligible for the study. Amikacin was administered intravenously during a 60-min infusion period. Three venous blood samples were taken from each patient during the first 48 h. Population pharmacokinetic parameter estimates were obtained using a population approach with the programme NONMEM. RESULTS: Data from 329 drug assay samples were obtained from 116 newborn patients (postmenstrual age [PMA] 38.3, range 32-42.4 weeks; weight 2.8, range 1.6-3.8 kg). Measured amikacin concentrations ranged from 0.8 to 56.4 mg/L. A 2-compartment model with linear elimination produced a good fit of the data. Estimated parameters for a typical subject (2.8 kg, 38.3 weeks) were clearance (Cl = 0.16 L/h), intercompartmental clearance (Q = 0.15 L/h), volume of distribution of the central compartment (Vc = 0.98 L) and peripheral volume of distribution (Vp = 1.23 L). Total bodyweight, PMA and the presence of sepsis positively influenced Cl. Plasma creatinine concentration and circulatory instability (shock) negatively influenced Cl. CONCLUSION: Our main results confirm previous findings showing that weight, PMA and renal function are relevant factors influencing newborn amikacin pharmacokinetics. In addition, current results showed that pathophysiological states of critically ill neonates, such as sepsis and shock, were associated with opposite effects in amikacin clearance and should be considered in dose adjustments.

Disposition of gentamicin and amikacin in extracorporeal membrane oxygenation using a heparin-coated filter: An in vitro assessment.

Disposition of gentamicin and amikacin during extracorporeal membrane oxygenation has not been addressed in in vitro models. The HLS Advanced 7.0® circuit with the Cardio Help® monitor, Getinge, was used. The 5-L central compartment (CC) was loaded with gentamicin and amikacin at a targeted concentration of 40 and 80 mg/L in the same bag prior connection to the circuit. Samples were collected in the CC, the inlet and outlet ports from 15 min to 6 h post-connection. Pharmacokinetic analyses were performed using the NeckEpur® method. Analysis of results of gentamicin and amikacin showed in the filter-pump block (i) the extremely low value of the extraction coefficients, (ii) similar values of the areas under the curve (AUCs) at the inlet and outlet ports, (iii) using the Wilcoxon matched pairs signed rank test no significant differences of the inlet-outlet concentrations in the filter-pump. In the whole system (i) the amounts recovered in the CC at the end of the 6-h session were not significantly different from the initial values, (ii) the extremely low values of the total clearance of gentamicin and amikacin from the CC in comparison with the measured simulated blood flowrate, (iii) the lack of significant time-concentration interactions in the CC and the inlet and outlet ports. These findings allow concluding no detectable adsorption of gentamicin and amikacin occurred in the HLS Advanced 7.0 circuit.

Amikacin Therapy in Japanese Pediatric Patients: Narrative Review.

Children show a very wide range of physical development processes. These changes impact pharmacokinetic (PK) variability in pediatric patients. Most PK studies have been conducted on the Caucasian population. Therefore, whether current evidence of how developmental change affects PK and exposure-response relationships applies to Japanese pediatric patients remains unclear. This narrative review focuses on amikacin therapy in Japanese pediatric patients and shows the relationship between amikacin concentrations and efficacy/toxicity. Ten relevant articles were identified. Of these, nine articles were published in the 1980s. All studies reported a maximum concentration (Cmax) and minimum concentration (Cmin) of amikacin. Overall, articles reporting PK/pharmacodynamic (PD) indices and minimum inhibitory concentration (MIC) of isolated bacteria in Japanese pediatric patients is lacking, whereas all patients recovered from an infection state and showed negative cultures. Five of the included studies reported the association between Cmin and toxicity. The Cmin in three of four patients who developed toxicity was above 10 mg/L. This narrative review shows that further PK study of amikacin in Japanese pediatric patients is necessary. In particular, the pursuit of knowledge of Cmax/MIC ratio is vital. On the other hand, this review demonstrates that the optimal Cmin for Japanese pediatric patients is below 10 mg/L as a candidate concentration. However, it is noted that the number of patients who developed toxicity is very small.

Evaluation of amikacin dosing schedule in critically ill elderly patients with different stages of renal dysfunction.

OBJECTIVES: Amikacin is still a widely used aminoglycoside for the treatment of life-threatening infections. The pharmacokinetic parameters of this antibiotic may be altered in critically ill conditions. Moreover, in the elderly population, pathophysiological changes affect these pharmacokinetic variables, making it difficult to predict the appropriate dose and dosing schedule for amikacin. This study aimed to characterise the pharmacokinetics of amikacin in critically ill elderly patients with renal dysfunction, and to evaluate if the available dose adjustment schedules dependent on renal function would be appropriate for empirical dosing. METHODS: Critically ill patients aged >60 years with a creatinine clearance of >20 mL/min in need of treatment with amikacin were randomly enrolled. All the patients received approximately 25 mg/kg amikacin. The patients were then divided into three groups according to the stages of their renal dysfunction based on creatinine clearance, and the optimum time to re-dosing was calculated for each group. The pharmacokinetic parameters of the patients were calculated and estimated as population pharmacokinetic data. RESULTS: Of 30 patients, only 20% attained the target peak levels of amikacin of >64 mg/L. In addition, the mean volume of distribution was 0.47 L/kg. There was a poor correlation between amikacin clearance and creatinine clearance. The difference in amikacin half-life was not statistically significant among any of the stages of renal impairment. CONCLUSIONS: The initial dosing of amikacin in critically ill elderly patients should not be reduced, even in the context of renal impairment. Regarding the dose adjustment in renal impairment, dosing intervals estimation, no decision can be made based on the creatinine clearance and the first dose individualisation method in terms of the two-sample measurements may be considered as an appropriate strategy.

Relationship between amikacin pharmacokinetics and biological parameters associated with organ dysfunction: a case series study of critically ill patients with intra-abdominal sepsis.

OBJECTIVES: This study aimed to evaluate the relationship between amikacin pharmacokinetics and the biomarkers associated with organ dysfunction in critically ill patients with intra-abdominal sepsis. METHODS: A case series involving critically ill patients with intra-abdominal sepsis who received an amikacin loading dose of 20-25 mg/kg intravenous infusion was studied. The 1-, 2-, 4-, 6- and 24-hour amikacin serum concentrations were measured to calculate the pharmacokinetic parameters. The Sequential Organ Failure Assessment (SOFA) score, white blood cells, neutrophil to lymphocyte ratio, platelet count, serum creatinine, creatinine clearance, bilirubin, partial pressure of oxygen to fraction of inspired oxygen ratio, serum albumin, procalcitonin, lactate level, erythrocyte sedimentation rate (ESR) and C-reactive protein were recorded. A linear regression analysis was performed to examine the relationship between the amikacin pharmacokinetics and the biological parameters. RESULTS: Twenty-one patients were studied. A significant correlation was found between the volume of distribution and ESR (p<0.05, r=0.844). Moreover, drug clearance had a significant inverse correlation with serum lactate (p<0.05, r=-0.603). No other significant correlations were found. CONCLUSIONS: ESR and serum lactate were identified as useful predictors of amikacin pharmacokinetics in critically ill patients with intra-abdominal sepsis and may help guide the selection of appropriate empirical dosing.

Breaking the barriers for the delivery of amikacin: Challenges, strategies, and opportunities.

Hypodermic delivery of amikacin is a widely adopted treatment modality for severe infections, including bacterial septicemia, meningitis, intra-abdominal infections, burns, postoperative complications, and urinary tract infections in both paediatric and adult populations. In most instances, the course of treatment requires repeated bolus doses of amikacin, prolonged hospitalization, and the presence of a skilled healthcare worker for administration and continuous therapeutic monitoring to manage the severe adverse effects. Amikacin is hydrophilic and exhibits a short half-life, which further challenges the delivery of sufficient systemic concentrations when administered by the oral or transdermal route. In this purview, the exploitation of novel controlled and sustained release drug delivery platforms is warranted. Furthermore, it has been shown that novel delivery systems are capable of increasing the antibacterial activity of amikacin at lower doses when compared to the conventional formulations and also aid in overcoming the development of drug-resistance, which currently is a significant threat to the healthcare system worldwide. The current review presents a comprehensive overview of the developmental history of amikacin, the mechanism of action in virulent strains as well as the occurrence of resistance, and various emerging drug delivery solutions developed both by the academia and the industry. The examples outlined within the review provides significant pieces of evidence on novel amikacin formulations in the field of antimicrobial research paving the path for future therapeutic interventions that will result in improved clinical outcome.

Quantification and Explanation of the Variability of First-Dose Amikacin Concentrations in Critically Ill Patients Admitted to the Emergency Department: A Population Pharmacokinetic Analysis.

BACKGROUND: There may be a difference between the determinants of amikacin exposure in emergency department (ED) versus intensive care (ICU) patients, and the peak amikacin concentration varies widely between patients. Moreover, when the first dose of antimicrobials is administered to septic patients admitted to the ED, fluid resuscitation and vasopressors have just been initiated. Nevertheless, population pharmacokinetic modelling data for amikacin in ED patients are unavailable. OBJECTIVE: The aim of this study was to quantify the interindividual variability (IIV) in the pharmacokinetics of amikacin in patients admitted to the ED and to identify the patient characteristics that explain this IIV. METHODS: Patients presenting at the ED with severe sepsis or septic shock were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg intravenously. Blood samples were collected at 1, 6 and 24 h after the onset of the first amikacin infusion. Data were analysed using nonlinear mixed-effects modelling. RESULTS: A two-compartment population pharmacokinetic model was developed based on 279 amikacin concentrations from 97 patients. The IIV in clearance (CL) and central distribution volume (V1) were 71% and 26%, respectively. Body mass index (BMI), serum total protein level, serum sodium level, and fluid balance 24 h after amikacin administration explained 30% of the IIV in V1, leaving 18% of the IIV unexplained. BMI and creatinine clearance according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 24 h after amikacin administration explained 46% of the IIV in CL, and 39% remained unexplained. CONCLUSION: The IIV of amikacin pharmacokinetics in ED patients is large. Higher doses may be considered in patients with low serum sodium levels, low total protein levels, or a high fluid balance. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02365272.

To Estimate or to Forecast? Lessons From a Comparative Analysis of Four Bayesian Fitting Methods Based on Nonparametric Models.

ABSTRACT: Using pharmacokinetic (PK) models and Bayesian methods in dosing software facilitates the analysis of individual PK data and precision dosing. Several Bayesian methods are available for computing Bayesian posterior distributions using nonparametric population models. The objective of this study was to compare the performance of the maximum a posteriori (MAP) model, multiple model (MM), interacting MM (IMM), and novel hybrid MM(HMM) in estimating past concentrations and predicting future concentrations during therapy. Amikacin and vancomycin PK data were analyzed in older hospitalized patients using 2 strategies. First, the entire data set of each patient was fitted using each of the 4 methods implemented in BestDose software. Then, the 4 methods were used in each therapeutic drug monitoring occasion to estimate the past concentrations available at this time and to predict the subsequent concentrations to be observed on the next occasion. The bias and precision of the model predictions were compared among the methods. A total of 406 amikacin concentrations from 96 patients and 718 vancomycin concentrations from 133 patients were available for analysis. Overall, significant differences were observed in the predictive performance of the 4 Bayesian methods. The IMM method showed the best fit to past concentration data of amikacin and vancomycin, whereas the MM method was the least precise. However, MM best predicted the future concentrations of amikacin. The MAP and HMM methods showed a similar predictive performance and seemed to be more appropriate for the prediction of future vancomycin concentrations than the other models were. The richness of the prior distribution may explain the discrepancies between the results of the 2 drugs. Although further research with other drugs and models is necessary to confirm our findings, these results challenge the widely accepted assumption in PK modeling that a better data fit indicates better forecasting of future observations.

Imine bond formation as a tool for incorporation of amikacin in self-emulsifying drug delivery systems (SEDDS).

AIM: The aim was to develop a self-emulsifying drug delivery system (SEDDS) for amikacin via imine bond formation with hydrophobic aldehydes. METHODS: Trans-2, cis-6-nonadienal, trans-cinnamaldehyde, citral and benzaldehyde were conjugated to amikacin at pH 8.5. Based on results of precipitation efficiency, Fourier-transform infrared spectroscopy (FTIR) and NMR analysis, amikacin-trans-cinnamaldehyde conjugates were further characterized regarding log Poctanol/water via HPLC. The release of amikacin from the amikacin-trans-cinnamaldehyde conjugates was examined through in vitro incubation with bovine serum albumin (BSA). SEDDS containing the amikacin-trans-cinnamaldehyde conjugates were tested regarding mean droplet size (MDS), polydispersity index (PDI), log DSEDDS/release medium and cell viability. RESULTS: Trans-cinnamaldehyde formed the most hydrophobic conjugates with amikacin whereas benzaldehyde did not form hydrophobic conjugates at all. Imine bond formation was confirmed by FTIR and NMR analysis. The highest increase in log P was achieved for the amikacin-trans-cinnamaldehyde conjugate in a molar ratio of 1:5, shifting from -8.58 up to 1.59. Incubation of this conjugate with BSA led to the formation of BSA-trans-cinnamaldehyde releasing in turn amikacin. SEDDS based on Capmul MCM, Cremophor EL and propylene glycol containing the conjugate demonstrated a MDS of 61.4 nm and PDI of 0.265. Log DSEDDS/release medium was calculated to be 3.38. Cell viability studies showed very good tolerability of conjugate loaded SEDDS in concentrations of 0.1% - 0.5%. CONCLUSION: Imine bond formation of amikacin with trans-cinnamaldehyde and the incorporation of the resulting conjugate into SEDDS represents a promising strategy for oral delivery of amikacin.